4-2988772-G-T

Variant names:

• chr4-2988772-G-T
• rs2960306
• NM_182982.3:c.194G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_182982.3(GRK4):​c.194G>T​(p.Arg65Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.343 in 1,609,242 control chromosomes in the GnomAD database, including 99,042 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R65C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.38 (11749 hom., cov: 32)
  • Exomes 𝑓: 0.34 (87293 hom.)
• Consequence: GRK4 NM_182982.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.34
• Publications: 112 publications found

Genes affected

GRK4 (HGNC:4543): (G protein-coupled receptor kinase 4) This gene encodes a member of the guanine nucleotide-binding protein (G protein)-coupled receptor kinase subfamily of the Ser/Thr protein kinase family. The protein phosphorylates the activated forms of G protein-coupled receptors thus initiating its deactivation. This gene has been linked to both genetic and acquired hypertension. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2013]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.7048926E-4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRK4	NM_182982.3	c.194G>T	p.Arg65Leu	missense_variant	Exon 3 of 16	ENST00000398052.9	NP_892027.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRK4	ENST00000398052.9	c.194G>T	p.Arg65Leu	missense_variant	Exon 3 of 16	1	NM_182982.3	ENSP00000381129.4
GRK4	ENST00000345167.10	c.98G>T	p.Arg33Leu	missense_variant	Exon 2 of 15	1		ENSP00000264764.8
GRK4	ENST00000504933.1	c.194G>T	p.Arg65Leu	missense_variant	Exon 3 of 15	1		ENSP00000427445.1
GRK4	ENST00000398051.8	c.98G>T	p.Arg33Leu	missense_variant	Exon 2 of 14	1		ENSP00000381128.4

Frequencies

GnomAD3 genomes AF: 0.380 AC: 57778 AN: 151888 Hom.: 11726 Cov.: 32

Gnomad AFR AF: 0.501

Gnomad AMI AF: 0.402

Gnomad AMR AF: 0.297

Gnomad ASJ AF: 0.282

Gnomad EAS AF: 0.0916

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.453

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.356

Gnomad OTH AF: 0.352

GnomAD2 exomes AF: 0.322 AC: 81000 AN: 251300 AF XY: 0.315

Gnomad AFR exome AF: 0.496

Gnomad AMR exome AF: 0.303

Gnomad ASJ exome AF: 0.293

Gnomad EAS exome AF: 0.0879

Gnomad FIN exome AF: 0.438

Gnomad NFE exome AF: 0.358

Gnomad OTH exome AF: 0.337

GnomAD4 exome AF: 0.339 AC: 493810 AN: 1457236 Hom.: 87293 Cov.: 31 AF XY: 0.335 AC XY: 242584 AN XY: 725060

African (AFR) AF: 0.504 AC: 16831 AN: 33384

American (AMR) AF: 0.302 AC: 13507 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 7621 AN: 26090

East Asian (EAS) AF: 0.0960 AC: 3807 AN: 39676

South Asian (SAS) AF: 0.187 AC: 16121 AN: 86180

European-Finnish (FIN) AF: 0.429 AC: 22869 AN: 53252

Middle Eastern (MID) AF: 0.359 AC: 2068 AN: 5756

European-Non Finnish (NFE) AF: 0.353 AC: 391327 AN: 1107974

Other (OTH) AF: 0.326 AC: 19659 AN: 60234

GnomAD4 genome AF: 0.381 AC: 57850 AN: 152006 Hom.: 11749 Cov.: 32 AF XY: 0.378 AC XY: 28089 AN XY: 74276

African (AFR) AF: 0.501 AC: 20780 AN: 41462

American (AMR) AF: 0.297 AC: 4528 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.282 AC: 976 AN: 3460

East Asian (EAS) AF: 0.0915 AC: 474 AN: 5182

South Asian (SAS) AF: 0.182 AC: 881 AN: 4828

European-Finnish (FIN) AF: 0.453 AC: 4768 AN: 10514

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.356 AC: 24223 AN: 67972

Other (OTH) AF: 0.350 AC: 739 AN: 2112

Alfa AF: 0.354 Hom.: 49108

Bravo AF: 0.376

TwinsUK AF: 0.339 AC: 1256

ALSPAC AF: 0.348 AC: 1340

ESP6500AA AF: 0.492 AC: 2167

ESP6500EA AF: 0.359 AC: 3086

ExAC AF: 0.326 AC: 39524

Asia WGS AF: 0.189 AC: 657 AN: 3478

EpiCase AF: 0.357

EpiControl AF: 0.352

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.065	.;T;.;.
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.53	T;T;T;T
MetaRNN	Benign	0.00047	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.0	.;N;.;N
PhyloP100		3.3
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	3.3	N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.30	T;T;T;T
Sift4G	Benign	0.46	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.17
MPC		0.073
ClinPred		0.021	T
GERP RS		5.6
Varity_R		0.12
gMVP		0.24
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2960306; hg19: chr4-2990499; COSMIC: COSV61668294;